K. Tarkiainen, M. T. Holmberg, A. Tornio, M. Neuvonen, P. J. Neuvonen, J. T. Backman, M. Niemi; University of Helsinki, Helsinki, Finland

BACKGROUND: Carboxylesterase 1 (CES1) hydrolyses about 90% of the prodrug clopidogrel to an inactive carboxylic acid metabolite. In vitro studies have shown that CES1 single nucleotide variations (SNV), such as c.428G>A (p.Gly143Glu, rs71647871), can markedly affect clopidogrel metabolism.
METHODS: We studied the pharmacokinetics and pharmacodynamics of a 600 mg oral dose of clopidogrel in 10 carriers and 12 noncarriers of the CES1 c.428G>A SNV. Clopidogrel and its carboxylic acid, acyl-β-D-glucuronide, and active cis 5-thiol metabolite plasma concentrations and platelet aggregation were measured for up to 12 hours.
RESULTS: The clopidogrel carboxylic acid to clopidogrel area under the plasma concentration-time curve from 0 h to infinity (AUC0-∞) ratio was 53% smaller in CES1 c.428G/A carriers than in noncarriers (P=0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0-∞ of clopidogrel and its active cis 5-thiol metabolite were 123% (P=0.004) and 67% (P=0.009) larger in the c.428G/A carriers than in noncarriers. Consistent with the pharmacokinetic findings, both the average inhibition of P2Y12-mediated platelet aggregation 0-12 h after clopidogrel intake and the maximum observed platelet inhibition were 19 percentage points higher in the c.428G/A carriers than in noncarriers (P=0.036 and P=0.041, respectively).
CONCLUSION: Clopidogrel pharmacokinetics is highly sensitive to genetic variation in CES1 activity, indicating that clopidogrel can be used as a CES1 probe substrate in humans. The CES1 c.428G>A SNV increases clopidogrel active cis 5-thiol metabolite concentrations and antiplatelet effects by reducing the hydrolysis of parent clopidogrel to inactive metabolites. Therefore, the CES1 c.428A allele may increase clopidogrel efficacy and bleeding risk.